SUMMARY Conventional wisdom says that antioxidants should lower cancer risk by neutralizing cell- damaging, cancer-causing oxidative stress. However, despite the compelling biochemical evidence that ties oxidative damage to carcinogenesis for in vitro systems, almost all large randomized clinical trials have shown that antioxidant supplementation provides no clear benefit and even increases cancer risk. These disappointing and seemingly contradictory results have puzzled the public and researchers for decades. Even more controversial is whether antioxidant supplementation is safe and effective for cancer survivors. An estimated 15.5 million Americans in 2016 were cancer survivors, and up to 81% of them used antioxidant supplements to promote healing. However, we do not understand whether and to what extent post-treatment oxidative stress is associated with cancer prognosis. We recently conducted a molecular epidemiological study of colorectal cancer (CRC). We found the first piece of evidence in humans that the association between oxidative stress and CRC risk was bidirectional, with both beneficial and deleterious effects. Moreover, these bidirectional effects were time-dependent. Specifically, in earlier phases of cancer development, high oxidative stress was associated with increased risk of CRC, whereas in later phases, it was associated with decreased risk. Correspondingly, we found that the association between antioxidant intake and CRC risk was also time- dependent and varied by baseline oxidative stress. In the pilot study, we found that among patients with more advanced cancer, their systemic levels of oxidative stress were actually lower. Furthermore, cancer patients with higher post-treatment levels of oxidative stress had odds of living longer, after comprehensively adjusting for clinical parameters. In this proposed study, we will conduct a large case-cohort study, building upon three Asian and European cohorts to determine whether our novel findings?the time-dependent and bidirectional effects of oxidative stress and antioxidants on CRC, first observed in Chinese women (discovery phase)?can be replicated in both sexes and in different ethnic populations (replication phase). Comprehensive assessments of oxidative stress in pre-diagnostic urine samples will be performed. We will also conduct a follow-up study of CRC cases from whom both pre-diagnostic and post-treatment urine samples have been collected. We will examine whether higher levels of systemic post-treatment oxidative stress are associated with better CRC survival, while comprehensively accounting for pre-diagnostic oxidative stress and other clinical parameters. We expect that this study, with its focus on the time-dependent and bidirectional association between oxidative stress and CRC, will provide novel insights into the role of oxidative stress in carcinogenesis, the first evidence linking oxidative stress and clinical outcomes of CRC, and much needed information for identification of population subsets for chemoprevention. Thus, this study will have high translational potential to lead to tailored strategies for CRC prevention and patient care.